There is growing evidence that MBCT and MBSR have efficacy for acute psychiatric conditions, including hard- to-treat ones like posttraumatic stress disorder (PTSD), treatment-resistant depression, and generalized anxiety disorder (GAD). However, specific mechanisms are not understood, nor is whether mechanisms are shared with other therapies (e.g. exposure, behavioral activation), or are distinct and potentially complementary. Elucidating MBCT mechanisms can enhance ongoing refinement and optimal targeting. Psychological mechanisms of MBCT involve ?decentering?, attentional training increases metacognitive awareness, which can reduce over-personalization and negative reactivity, experiential avoidance, rumination, and psychiatric symptoms. PTSD and depression are associated with aberrant intrinsic neural connectivity, e.g. between default mode network (DMN), salience network (SN) and attentional control networks. Converging evidence suggests that MBCT/MBSR can alter these connectivities to enhance mental and physical health. For example, MBCT/MBSR increases connectivity of DMN with attention networks nodes (e.g. DLPFC), with associated reductions in PTSD symptoms and plasma IL-6. MBCT/MBSR also decreases functional connectivity between DMN (vmPFC, subgenual ACC) and SN (insula, amygdala). These findings suggest MCBT may redirect attentional resources in ways that lead to a ?de-automatization? or partial uncoupling of aversive perceptual signals from rapid/automatic behavioral response systems that can be costly and maladaptive when overused, and which may represent core transdiagnostic mechanisms underlying mood, anxiety, and trauma disorders. We hypothesize that MBCT/MBSR leads to increased DMN-attention network connectivity (e.g. PCC-DLPFC, vmPFC-DLPFC) and increased meta-cognitive attentional capacity, contextualizing, and attention shifting (H1), and decreased DMN-SN connectivity (e.g. vmPFC-insula), leading to increased ability to depersonalize potentially aversive cues and interoceptive signals, reducing negative reactivity (H2). We will test these hypotheses in treatment of PTSD, which provides an useful model system, since the networks known to be impacted by MBCT are also known to be involved in PTSD, and MBCT is known to reduce PTSD symptoms. Our R61 will test network target engagement by MBCT (H1 or H2) in PTSD patients (N=42), using pre-post MBCT seed-based and whole brain connectomics (a) in resting state functional connectivity and (b) during self-referential processing. ?Go-criteria? will be increased DMN-attention network or decreased DMN-SN connectivity post MBCT. Our R33 will use an RCT of MBCT (N=53) vs a Prolonged Exposure therapy in vivo exposure group (N=53) to validate target engagement by MBCT and mediation of symptom improvement, and whether mechanisms are different from those engaged by PE in vivo exposure. We will test for treatment group differences in network target engagement and its mediation of changes in decentering, PTSD symptoms, acceptance, stress reactivity, functionality, and quality of life.